Dexmedetomidine Pharmacokinetics in Neonates with Hypoxic-Ischemic Encephalopathy Receiving Hypothermia.

Ryan M Mcadams,Danny D Shen,Daniel Pak,Bojan Lalovic,Brian Phillips

doi:10.1155/2020/2582965

Abstract

Dexmedetomidine is a promising sedative and analgesic for newborns with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH). Pharmacokinetics and safety of dexmedetomidine were evaluated in a phase I, single-center, open-label study to inform future trial strategies. We recruited 7 neonates ≥36 weeks' gestational age diagnosed with moderate-to-severe HIE, who received a continuous dexmedetomidine infusion during TH and the 6 h rewarming period. Time course of plasma dexmedetomidine concentration was characterized by serial blood sampling during and after the 64.8 ± 6.9 hours of infusion. Noncompartmental analysis yielded descriptive pharmacokinetic estimates: plasma clearance of 0.760 ± 0.155 L/h/kg, steady-state distribution volume of 5.22 ± 2.62 L/kg, and mean residence time of 6.84 ± 3.20 h. Naive pooled and population analyses according to a one-compartment model provided similar estimates of clearance and distribution volume. Overall, clearance was either comparable or lower, distribution volume was larger, and mean residence time or elimination half-life was longer in cooled newborns with HIE compared to corresponding estimates previously reported for uncooled (normothermic) newborns without HIE at comparable gestational and postmenstrual ages. As a result, plasma concentrations in cooled newborns with HIE rose more slowly in the initial hours of infusion compared to predicted concentration-time profiles based on reported pharmacokinetic parameters in normothermic newborns without HIE, while similar steady-state levels were achieved. No acute adverse events were associated with dexmedetomidine treatment. While dexmedetomidine appeared safe for neonates with HIE during TH at infusion doses up to 0.4 μg/kg/h, a loading dose strategy may be needed to overcome the initial lag in rise of plasma dexmedetomidine concentration.

Highlights

Worldwide, hypoxic-ischemic encephalopathy (HIE) is a leading cause of neonatal brain injury and neonatal mortality [1]
therapeutic hypothermia (TH) had already begun in all 7 neonates by the time parental consent was obtained; dexmedetomidine infusions were initiated at an average of 14 ± 6.5 h after TH was started
Differences in dexmedetomidine pharmacokinetics were observed in the current small cohort of newborns with HIE undergoing TH compared to reported literature data for normothermic neonates without HIE

Summary

Introduction

Hypoxic-ischemic encephalopathy (HIE) is a leading cause of neonatal brain injury and neonatal mortality [1]. In high-income countries, therapeutic hypothermia (TH) is the standard therapy to mitigate brain damage in newborns with HIE. While TH appears to increase survival without increasing major disability in survivors, 1 in 4 neonates with moderate-to-severe HIE die despite receiving TH [2]. Newborns with moderate-to-severe HIE often have multiorgan failure and may demonstrate seizures, respiratory failure, and cardiovascular instability. Ey commonly receive morphine for sedation and to prevent shivering [3]. Efficacy of morphine as an adjunctive therapy during TH has not been evaluated in clinical trials. Morphine requires dosing adjustments to avoid toxicity due to altered pharmacokinetics during TH [4]. Safety concerns with morphine include short-term side effects such as depressed ventilation and questionable effects on long-term neurodevelopmental outcomes [5,6,7]

Methods

Results

Conclusion